I. Patterns and Determinants of Arterial Aging: A. New findings from the BLSA have shown longitudinal association between uric acid and pulse wave velocity (Canepa, 2016); this association was observed in men but not women. These findings shed light into the previously observed gender differences in arterial stiffening with aging. B. New findings from the Sardinia study have shown no effect of subclinical hypothyroidism on intimal medial thickness, a manifestation of arteria aging (Delitala, 2016) C. New findings from the SardiNIA study reported Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function (Scuteri 2016) Previous findings from SardiNIA project have shown significant gender differences in the effect of white coat and masked hypertension on arterial structure (Scuteri 2016). Previous Longitudinal insight into the complex nature of arterial aging. Findings from the Baltimore Longitudinal Study on Aging (BLSA) revealed a non-linear, longitudinal increase in pulse wave velocity (PWV) with aging that is more pronounced in men (AlGhatrif et al., 2013). Analysis of longitudinal data from SardiNIA project showed similar results, but in addition it showed an interesting separation between the longitudinal trajectories of PWV and SBP in men with advancing age (Scuteri 2014); this suggests that other age-related process, such as aortic dilatation, might blunt the effect of wall stiffening and cause the separation of PWV and SBP. To test the hypothesis that aortic dilatation contributes to the separation between PWV and SBP in men, preliminary analysis of data from BLSA confirmed the separation between SBP and PWV in older men, and showed greater rates of longitudinal aortic dilatation among men, which supports our hypothesis; these results were presented as an oral presentation during the at the American Heart Association Scientific Sessions, 2013, Dallas, TX. To examine earlier manifestation of arterial stiffness with aging, we analyzed data on carotid diameter from the SardiNIA project, we found earlier decline in distensibility between the age of 30 to 50 is a result of impaired recoil rather than restricted expansion; these results were presented as an oral presentation during the American College of Cardiology meeting 2014, Washington D.C. To examine the underlying causes of the more pronounced aortic dilatation in older men, we performed an analysis of data from Taiwan project; interestingly, we have observed that the magnitude of pressure wave reflection was associated with larger aortic diameter in men but not in women, which might contribute to the greater aortic dilatation in men with aging; this manuscript is in preparation for submission and the abstract was presented as an oral presentation at the North American Artery Society meeting, 2013. These interesting findings support our working hypothesis of major role of age-associated process that is independent from other traditional cardiovascular risk factors. These findings along were reviewed along with other reports in a review article published in Current Hypertension Reports (AlGhatrif and Lakatta 2015). B. Genetic and Environmental Underpinnings of Accelerated Cardiovascular Aging -Genetic determinates: Earlier results from the SardiNIA study have revealed a potential role of the Col4A1 gene (Tarasov 2009) and a second genetic element located in a desert region of the genome (Mitchell 2012), findings which have been confirmed in replication studies and larger Consortia-based analysis. Work is in progress to examine genetic determinants of the longitudinal change in PWV. -Environmental determinants: Another report using SardiaNIA cohort showed no evidence of an effect o f subclinical hypothyroidism on arterial stiffness (Delitala 2015). Except for blood pressure, we have previously found a minimal role of traditional cardiovascular risk factors in the progression of arterial stiffness (AlGhatrif et al., 2013). We have also found that central obesity might introduce bias to PWV measurements (Canepa et al. 2014). In addition, we have found that vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness (Ameri et al. 2014). We have also found that bone mineral density plays a role in the inverse relationship between body size and aortic calcification (Canepa et 2014). Projects examining the role of low-grade inflammation in arterial stiffness using data from the BLSA and the SardiNIA projects are in progress. As far as cardiac funciton, Results from the BLSA have shown that visceral, rather than subcutaneous fat, is associated with worse myocardial diastolic dysfunction (M Canepa, Strait, et al., 2013. In addition, the VALIDATE study, which will assess the factors leading to unhealthy vascular aging as measured by PWV, intimal medial thickness, coronary calcium scoring, among other tests, is currently in final stages of completing the follow-up visit. Another project has been started aiming to assess age-associated changes in regional adiposity and novel cardiovascular risk factors such as coronary endothelial function and myocardial triglyceride content using magnetic resonance imaging. II. Advanced CV phenotyping: To further examine the complex nature of arterial aging, we have initiated a program focused on advanced mathematical analysis of cardiovascular physiological signals including pressure, flow, and geometry signals to derive parameters that better represent the functional status of the CV in a given person and how it changes with aging. We recruited a post-doctoral fellow with training in biomedical engineering and established collaborations with international experts to develop advanced software to analyze CV traits collected from BLSA and SardiNIA participants. Great efforts have been made to compile raw data from echocardiography, Doppler, and applanation tonometry. Variables generated include derived central blood pressures, wave reflection parameters, aortic and carotid characteristic impedance, carotid geometric phenotype, carotid total, systolic, and diastolic flow rates, and CV mechanical power and efficiency. Preliminary data have showed that cardiac efficiency declines with aging and that this decline is attributed in part to increased aortic impedance and early arrival of wave reflection, but with reflection magnitude per se. These results were accepted for presentation at the American Heart Association meeting 2016. A more comprehensive analysis is being performed and a manuscript will be written. III. The impact of arterial aging on cardiac geometry and function: We have previously shown an early contribution of arterial wave reflection on myocardial diastolic dysfunction before the progression of hypertension (Canepa, AlGhatrif, et al., 2013). We have examined the prevalence and correlates of subaortic septal thickening and found that it increase with age without any effect on exercise capacity. A more extensive analysis will be performed once the arterial phenotypic evaluation is completed. Preliminary analyses of data analyzed so far have shown a decline in cardiac energy efficiency with aging and that it was negatively associated with early arrival of the reflected wave and positively with the reflection index. This data has been submitted for presentation at the American Heart Association meeting 2015. Analysis of a large sample is currently being performed. The relationship between arterial stiffness and the development of heart failure was reviewed in an editorial (Canepa and AlGhatrif 2016) IV. The Impact of arterial aging on end organs. New findings from the BLSA have shown that (AlGhatrif 2017), in the absence of peripheral arterial disease, lower ABI was associated with a decline in mitochondrial e